The present invention is directed to cationic radiopharmaceutical complexes of technetium-99m (Tc-99m or .sup.99m Tc) and particularly to cationic complexes of Tc-99m with N-substituted 3-hydroxy-4-pyridinones. Such cationic complexes are useful in diagnostic scintigraphic imaging.
Other heterocyclic complexes of radioactive metals have previously been reported in patents and scientific literature. For example:
Baker et al., in U.S. Pat. No. 3,981,980, disclose a diagnostic substance for cholescintigraphy which is formed by the reaction of pyridoxal and amino acids, labelled with a radionuclide, in pyrogen-free water, the reaction product being adjusted to a pH of 8 to 9 and then autoclaved and cooled to produce a sterile, pyrogen-free non-antigenic solution for injection for biliary scanning.
Frank et al., in U.S. Pat. No. 4,193,979 disclose complexes of the compound sodium 3-[[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl] -amino]carbonyl]-2-pyridine carboxylic acid (and related compounds) with radioactive technetium-99m. These complexes are disclosed for use as radiopharmaceutical imaging agents, and in particular, these complexes are useful as gallbladder and liver imaging agents.
Thakur, in U.S. Pat. No. 4,443,426, discloses an agent for labelling blood cells comprising a complex of a radioactive metal (e.g., Tc-99m) with an N-oxide of pyridine. This complex is disclosed for use for the in vivo imaging of blood cells for diagnostic purposes.
Feld et al., in U.S. Pat. No. 4,714,065, disclose technetium-99m labeled dioxime complexes for imaging the myocardium, brain and hepatobiliary systems of humans and other mammalian species.
Srivastava et al., in U.S. Pat. No. 4,764,598, disclose a class of radiolabeled compounds as imaging agents with rapid brain uptake, good brain/blood radioactivity ratios, and long retention times. The imaging agents comprise radioiodinated aromatic amines attached to dihydropyridine carriers.
Benedict et al., in U.S. Pat. No. 4,830,847, disclose diphosphonate-derived macromolecules, such as proteins, as being suitable for use as technetium-99m based scanning agents. The scanning agents are prepared by combining Tc-99m in a +3, +4 and/or +5 oxidation state with the diphosphonate derivatized macromolecules. Also disclosed are pharmaceutical compositions containing these diphosphonate derivatized macromolecules and methods for scintigraphic imaging using these diphosphonate derivatized macromolecules labeled with Tc-99m.
Rocklage et al., in U.S. Pat. No. 4,842,845, disclose radioactive metal ion chelates of N,N'-bis-(pyridoxal-5-phosphate)-alkylenediamine- N,N'-diacetic acids, N,N'-bis-(pyridoxal-5-phosphate)-1,2-cycloalkylenediamine-N,N-diacetic acids, and N,N-bis-(pyridoxal-5-phosphate)-l,2-arylenediamine-N,N'-diacetic acids, the corresponding monophosphate compounds and monoacetic acid compounds, and their salts and esters. Preferred agents are technetium-99m and indium-111 ion chelates of N,N'-bis-pyridoxal-5- phosphate)ethylenediamine-N,N'-diacetic acid, N,N'-bis-(pyridoxal-5-phosphate)trans-1,2-cyclohexylene-diamine-N,N'-diace tic acid, N,N'-bis-(pyridoxal-5-phosphate)-trans-1,2- arylenediamine-N,N'-diacetic acid, and the soluble calcium salts thereof.
Benedict et al., in U.S. Pat. No. 5,011,913, disclose diphosphonate derivatized macromolecules, such as proteins, suitable for use as technetium-99m-based scanning agents. The scanning agents are prepared by combining Tc-99m in a +3, +4 and/or +5 oxidation state with the diphosphonate derivatized macromolecules. Also disclosed are pharmaceutical compositions containing these diphosphonate derivatized macromolecules and methods for scintigraphic imaging using these diphosphonate derivatized macromolecules labeled with Tc-99m.
The following literature references relate to heterocyclic complexes with various metals and contain disclosures of pyridinone or hydroxypyridinone complexes of metals such as aluminum, gallium or indium (but not technetium):
M. M. Finnegan et al., J. Amer. Chem. Soc., 108, 5033-5035 (1986) disclose a neutral water-soluble aluminum complex of 3-hydroxy-2-methyl-4H-pyran-4-one.
Kontoghiorghes et al., Inorganica Chimica Acta, 136, L11-L12 (1987) disclose the synthesis of iron chelators 1-alkyl-3-hydroxy-2-methylpyrid-4-ones.
Finnegan et al., Inorg. Chem., 26, 2171-2176, (1987) disclose neutral water-soluble post-transition metal chelate complexes of medical interest, specifically aluminum and gallium tris(3-hydroxy-4-pyronates).
Nelson et al., J. Am. Chem. Soc., 109, 4121-4123 (1987) disclose the exoclathrate Al(C.sub.7 H.sub.8 NO.sub.2).sup.3- 12H.sub.2 O.
Nelson et al., Inorg. Chem., 27, 1045-1051 (1988) disclose aluminum and gallium compounds of 3-hydroxy-4-pyridinones, their synthesis, characterization, and crystallography of these biologically active complexes.
Matsuba et al., Inorg. Chem., 27, 3935-3939 (1988) disclose neutral water-soluble indium complexes of 3-hydroxy-4-pyrones and 3-hydroxy-4-pyridinones.
Clevette et al., Inorg. Chem., 28, 2079-2081 (1989) disclose the complexation of aluminum with N-substituted 3-hydroxy-4-pyridinones.
Nelson et al., Inorg. Chem., 28, 3153-3157 (1989) disclose aluminum and gallium complexes of 1-ethyl-3-hydroxy-2-methyl-4-pyridinone as a new exoclathrae matrix.
Clevette et al., Inorg. Chem., 29, 667-672 (1990) disclose the solution chemistry of gallium and indium 3-hydroxy-4-pyridinone complexes in vitro and in vivo.
Zhang et al., Inorg. Chem., 30, 509-515 (1991) disclose lipophilic coordination compounds comprising aluminum, gallium, and indium complexes of 1-Aryl-3-hydroxy-2-methyl-4-pyridinones.
Finally, maltol and Kojic acid have recently been complexed with Tc-99m to form cationic scintigraphic complexes. See, Kanvinde et al., J. Nuclear Med., 31:908, Abst. No. 866 (1990).
None of the above cited patents or publications either teach or suggest the existence of the novel cationic technetium radiopharmaceutical complexes of the present invention or that such complexes would be useful diagnostic imaging agents.